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Lookup NU author(s): Michelle Moffat
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.Background: Collagen XVII is most typically associated with human disease when biallelic COL17A1 variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1 variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1 variants causing dominant non-syndromic AI is not widely recognised. Methods: Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1 variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth. Results: Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1 variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting. Conclusion: These results indicate that COL17A1 variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1 variants. We propose that patients with isolated AI or ERED, due to COL17A1 variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.
Author(s): Hany U, Watson CM, Liu L, Smith CEL, Harfoush A, Poulter JA, Nikolopoulos G, Balmer R, Brown CJ, Patel A, Simmonds J, Charlton R, Acosta De Camargo MG, Rodd HD, Jafri H, Antanaviciute A, Moffat M, Al-Jawad M, Inglehearn CF, Mighell AJ
Publication type: Article
Publication status: Published
Journal: Journal of Medical Genetics
Year: 2023
Pages: epub ahead of print
Online publication date: 18/11/2023
Acceptance date: 17/10/2023
Date deposited: 12/12/2023
ISSN (print): 0022-2593
ISSN (electronic): 1468-6244
Publisher: BMJ Publishing Group
URL: https://doi.org/10.1136/jmg-2023-109510
DOI: 10.1136/jmg-2023-109510
PubMed id: 37979963
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